The epithelium is the first line of defense of the airways against invading pathogens. Many of the non-specific defenses against such invaders arise from respiratory epithelial cells. Epithelial cells produce low molecular weight antimicrobial peptides, antibacterial enzymes, and antiproteases. In addition, secretory immunoglobulin A, a non-specific immunoglobulin defense, is trafficked into the airway via a specialized receptor, the polymeric immunoglobulin receptor (pIgR), that is expressed only on epithelial cells.
These epithelial defenses are breached early in the life of patients with cystic fibrosis (CF). Once live bacteria reach their surface, the epithelial cells direct the initial inflammatory response by releasing interleukin-8 (IL-8) and interleukin-6 (IL6) as well as reducing expression of interleukin-10 (IL-10). The chemoattractants, combined with increased expression of adhesin molecules for neutrophils, enhance inflammatory cell migration into the airways. Once there, the neutrophils, in an attempt to clear the bacteria, release lytic enzymes in the process. If the neutrophils remain adherent to the epithelium, these enzymes are released right at the epithelial surface. Both mechanical disruption of cells and even low concentrations of neutrophil elastase (NE) result in the greater release of pro-inflammatory mediators from the respiratory epithelium. Thus, the inflammatory response is further enhanced.
Several strategies to interrupt this cycle have been proposed. Augmenting the antibacterial defenses of the airway at the epithelial surface may be useful. Prevention of the escalation of the inflammatory responses engendered by the neutrophils migrating into the airway could be accomplished by preventing the action of elastase at the airway cell surface. Both antibiotics and antiproteases are available for clinical use. Unfortunately, the results of clinical studies examining the use of the antiprotease in patients with CF have been disappointing. The systemic administration of alpha.sub.1 -antitrypsin (A.sub.1 AT) is inefficient, and the levels achieved by the intravenous administration of the antiprotease are insufficient to inhibit the overwhelming amount NE in the lung of patients with CF. Aerosolized A.sub.1 AT should permit the direct delivery to the airways, but the antiprotease delivered by nebulization has been uneven and deposits the drug atop the mucus blanket rather than the critical site at the surface of the cell.
Thus there is a need in the art for methods to circumvent these difficulties and protect the respiratory epithelial cell surface.